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J Thorac Cardiovasc Surg 1998;116:386-390
© 1998 Mosby, Inc.

Cardiothoracic Transplantation

Ex vivo gene therapy prevents chronic graft vascular disease incardiac allografts

From the Departments of Cardiothoracic Surgery^a andPathology,^b Stanford University School of Medicine, FalkCardiovascular Research Building, Stanford, Calif.

Presented at the Thirty-third Annual Meeting of The American Societyof Transplant Physicians, Chicago, Ill., May 2-5, 1997.

Objective: We hypothesized that ex vivohyperbaric transfection of antisense oligodeoxynucleotides for blockade ofintercellular adhesion molecule–1, an important mediator of cell adhesionand T-cell co-stimulation, would reduce chronic graft vascular disease incardiac allografts.
Methods: PVG hearts underwent ex vivotransfection with antisense, reverse antisense intercellular adhesion molecule–1oligodeoxynucleotide (80 µmol/L), or saline solution at 3 atm pressure for45 minutes at 4° C and were transplanted heterotopically into ACI recipientswith or without treatment with intercellular adhesion molecule–1 (1A29) orleukocyte function associated antigen–1 (WT.1) monoclonal antibodies.Transfection efficiency was confirmed with fluorescein isothiocyanate–labeledoligodeoxynucleotides and fluorescent microscopy. Efficacy of intracellularadhesion molecule–1 blockade was assessed with the use ofimmunohistochemistry. Graft reperfusion injury was evaluated at 6 to 24 hours byneutrophil infiltration (myeloperoxidase [MPO]), cardiac edema (%wt/wt),and histologic injury (percent contraction band necrosis). Grafts fromrecipients treated with cyclosporine A (5 mg/kg per day, days 0 to 9) werescored for chronic graft vascular disease on postoperative day 90 ranging from 0(no involvement) to 4 (>50% vascular occlusion).
Results: Transfection was highly efficient (fluoresceinisothiocyanate–labeled oligodeoxynucleotides in 48% ± 5%of total myocardial nuclei) and effective at blocking intracellular adhesionmolecule–1 expression (positive area in allografts taken on postoperativeday 3 was reduced from 100% ± 0% to 52% ± 14%,n = 4). Blockade with antisenseoligodeoxynucleotides versus monoclonal antibodies was less effective atpreventing reperfusion injury while more effective at reducing chronic graftvascular disease (score 0.98 ± 0.48, P <0.05). Reverse antisense oligodeoxynucleotides and vector control (antisenseoligodeoxynucleotide infusion without pressure) groups failed to demonstratethis beneficial effect.
Conclusion:Hyperbaric transfection of antisense oligodeoxynucleotides proved highlyefficient, effective at blockade of intracellular adhesion molecule–1, anddemonstrated a sequence-specific reduction in chronic graft vascular disease.This highly targeted alteration of donor organ immunogenicity may have animportant future role in clinical immunosuppressive strategies. (J ThoracCardiovasc Surg 1998;116:386-96)

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